A gene-dosage effect for interleukin-4 receptor alpha-chain expression has an impact on Th2-mediated allergic inflammation during bronchopulmonary mycosis.
Interleukin (IL)-4 and IL-13 are key factors in the pathogenesis of bronchopulmonary mycosis induced in mice by infection with Cryptococcus neoformans. Both cytokines use the IL-4 receptor alpha-chain (IL-4Ralpha). In this study, we investigated the role played by IL-4Ralpha expression in susceptibility to pulmonary C. neoformans infection. IL-4Ralpha(-/-) mice were extremely resistant. To characterize the effect of IL-4Ralpha expression level on disease outcome, we generated IL-4Ralpha(+/-) first-generation (F1) mice. IL-4Ralpha(+/-) mice showed intermediate levels of IL-4Ralpha expression, in contrast to higher levels in wild-type mice and no expression in IL-4Ralpha(-/-) mice, indicating biallelic expression of the gene for IL-4Ralpha (Il4ra). Concomitant with intermediate IL-4Ralpha expression, F1 mice showed intermediate susceptibility associated with altered Th2/Th17 cytokine production, decreased immunoglobulin E levels, and reduced allergic inflammation. This indicates a gene-dosage effect of IL-4Ralpha expression on susceptibility to bronchopulmonary mycosis. These data provide the basis for novel therapies antagonizing IL-4Ralpha in Th2-related pulmonary infection and possibly also in asthma.
Müller
Uwe
U
Institute of Immunology, College of Veterinary Medicine, University of Leipzig, An den Tierkliniken 11, Leipzig, Germany.
Stenzel
Werner
W
Köhler
Gabriele
G
Polte
Tobias
T
Blessing
Manfred
M
Mann
Amrit
A
Piehler
Daniel
D
Brombacher
Frank
F
Alber
Gottfried
G
D000483:Alleles; D000818:Animals; D003453:Cryptococcosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit
D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit